1.0 INTRODUCTION

Aseptic filling process can be validated using
microbiological growth medium in place of the product. This process of validation also known as a media fill validation, normally includes
exposing the microbiological growth medium to product contact surface of
equipment, container closure system, and critical environments to closely
simulate the same exposure that the product itself will undergo at the time of processing or filling. The sealed
containers after filling with the medium are incubated to detect microbial growth for contamination at optimum temperature.

2.0 OBJECTIVE:

The
objective of the validation is to establish documented evidence that the process for aseptic processing of parenterals liquid/ophthalmic solution will
pass the acceptance criteria consistently, when performed as per the Standard Operating Procedures.

3.0 SCOPE:

The
Validation protocol provides the procedure for the Process Simulation
(Media Fill) for SVP line.

8.2 Frequency,
Duration, Number of runs & Fill Volume:

8.2.1 Media
fill trials must be performed on semi-annual basis for each aseptic process and
additional media fill trials should be performed in case of any change in
procedure, practices or equipment configuration.

8.2.2 Filled
units in Media Fill run should be 10,000 units or more. Fill minimum 3000
units in each production shift.

8.2.3 The
duration of Media Fill run must cover all the three operational shifts in each
run turn by turn including worst cases as stated in step No. 9.1.

8.2.4 Fill
volume for Media Fill run for SVP is 10 ml.

8.3 Environmental
Consideration:

8.3.1 Cleaning of Area must be done by using routine cleaning agent and disinfectant solution, as per latest SOP

8.3.2 Microbiological Environmental monitoring should be carried out to cover the
entire media fill program for manufacturing area by Settle plate, Active Air
sampling, Swab test and personnel monitoring as per the latest SOP.

8.4 Media:

8.4.2 The media must be passed the test for GPT as per SOP to promote the growth of
gram-negative and gram-positive bacteria and yeast and molds.

8.5 Incubation
and examination of filled units:

8.5.1 Incubate all media filled units in normal position after leak test at of
20 to 25ºC for 7 days. Incubation temperature should be maintained
within 22.5 ± 2.5ºC .

8.5.2 After completion of 7 days Incubation at 20 to 25ºC,
invert the units and incubate them at 30-35ºC for
next 7 days. Incubation temperature should be maintained within 32.5±2.5ºC
.

8.5.3 Each media filled unit should be examined by trained Microbiologist after 3rd day,
7th day, 10th day and 14th day.

8.5.4 All suspect units identified during the observation should be brought to the
immediate attention of the QC Microbiologist.

8.6 Interpretation
of Test Result:

8.6.1 Any contaminated unit should be considered objectionable and investigated. The
microorganism should be identified to species level.

8.6.2 The investigation should survey the possible causes of contamination.

8.6.3 When filled units up to 10000, one contaminated unit should result in an
investigation, including consideration of a repeat media fill.

9.0 VALIDATION
PROCEDURE

9.1 CIP
and SIP for SVP:

9.1.1 Carry
out cleaning of SVP mixing tank and holding tank along with product line and
bottle pack machine 3012 as per respective SOP for CIP.

9.1.2 At
the end of cleaning, collect last rinses sample from sampling point and send to
QC department with written information for testing of previous product traces.

9.1.3 After
getting approval report from QC, affix status label on the tank “READY FOR STERILIZATION”.

9.1.4 Immediately
carry out the sterilization of SVP holding tank along with final filter and
product line of bottle pack machine as per respective SOP.

9.1.5 After
Sterilization, affix a status label on the SVP line.

9.2 Dispensing
of Soybean Casein Digest Medium for 150 L batch size:

9.2.1 Give
raw material requisition slip in duplicate to store (either computerized or
manual) duly signed by Production Officer and Authorized by HOD (Production)

9.2.2 Enter
to dispensing room as per SOP for entry exit procedure to dispensing area.

9.2.3 Check
for the clearance of the area from any unwanted materials. Check for the
cleanliness of the area, LAF, weighing pan as per checklist. Put “ON” the
reverse LAF unit 15 minutes before dispensing of material.

9.2.4 Check
the availability of clean containers, SS scoops, pressure differentials, and
temperature & humidity should be not more than 25ºC and 45 to
60% RH respectively.

9.2.6 Take
the Approved Soybean Casein Digest Medium in pre-dispensing room, place on SS
pallet and check the label of container for correctness and Approval of
material.

9.2.7 Transfer
the material to Dispensing room, place the empty clean container on the balance
and record the tare weight. Press “ZERO” of the balance and weigh the required
quantity of material, note the weighed material and then remove the container
from balance and press Zero.

9.2.8 Close
the dispensed material, affix the weighing tag and transfer the material in
dispensed material storage room.

9.2.9 After
dispensing, put “OFF” the balance and LAF. Clean the surrounding area, balance
and spray with 70% IPA solution.

9.2.10 Reseal
the original container and shift to their original place.

9.3 Batch
Preparation 150 L:

9.3.1 Ensure
that the area and product line is clean and free from the traces of previous
product.

9.3.2 Recheck
the tag and gross weight of Soybean casein digest medium (SCDM) to be used for
manufacturing and ensure that they match as per entries made in the BMR
weighing sheet.

9.3.3 Check
the status board affixed on the tank “READY FOR USE”, also verify the records
and ensure that the bottom outlet valve of the mixing tank is closed.

9.3.4 Send
the entry point sample of WFI from the user point to QC department for testing
along with BMR.

9.3.5 On
approval of WFI sample from QC department, affix a status board on the Mixing
tank “UNDER MANUFACTURING” with Product name and B.No.

9.3.6 Collect
approx 50 L water for injection at 80 to 85ºC in a manufacturing
tank fitted with stirrer.

10.4.10 Arrange
the cassettes of vials lot wise in stainless steel trays vertically in vacuum leak testing
chamber tray and carry out the leak testing at 650 – 720 mm Hg for 30 minutes.
Do not use the leak vials for further media fill study.

10.4.11 After
leak test, transfer the goods vials in the clean plastic crates horizontally in
cassette from one above the other, lot wise separately.

10.5 Incubation
and Examination of Media Filled Units:

10.5.1 Incubate all media filled units in normal position after leak test at 20
to 25ºC for 7 days. Incubation temperature should be maintained
within 22.5 ± 2.5ºC.

10.5.2 After completion of 7 days Incubation at 20 to 25ºC, invert
the units and incubate them at 30-35ºC for next 7 days.
Incubation temperature should be maintained within 32.5 ±2.5ºC.

10.5.3 Each media filled unit should be examined by trained Microbiologist after 3rd day,
7th day, 10th day and 14th day.

10.5.4 All suspect units identified during the observation should be brought to the
immediate attention of the QC Microbiologist.

10.5.5 During incubation, if any unit found to be damaged should be recorded in media
fill observation format.

10.6 Interpretation
of Results:

10.6.1 When
filling fewer than 5,000 units, no contaminated units should be detected.

10.6.2 When
filling 5,000 to 1,0000 units :

(a) One contaminated
unit should result in an investigation, including consideration of a repeat
media fill ;

(b) Two
contaminated units are considered cause for revalidation, following
investigation.

10.6.3 When
filling more than 10,000 units:

(a) One contaminated
unit should result in an investigation;

(b) Two
contaminated units are considered cause for revalidation, following
investigation.

10.7 Failure
Investigation:

10.7.1 Any contaminated unit should be considered objectionable and investigated. The
microorganism should be identified to species level.

10.7.2 The investigation should survey the possible causes of contamination during
media fill trials i.e. Environmental, personnel and surface monitoring.

10.7.3 Based on the outcome of the investigation, assign the cause of failure is
assignable or not assignable.

10.7.5 If the cause is not assignable, then the process should be validated, as it is
a new process. Consecutive three-process simulation test should be performed to
demonstrate consistency and reliability on the sterile formulation manufacturing process to produce acceptable product.

3 comments:

after filtration of bulk scdm, the filtered scdm is send for sterility test. how this sterility test performed ? that is weather keeping the same filtered bulk in 30-35 degree temp, or by doing membrane filtration and keeping the membrane in both SCDM and FTGM? ............... I mean sterility testing for anaerobic organisms required or not?